Synthesis of enantiomerically pure isoxazolidine monomers for the preparation of β3-oligopeptides by iterative α-keto acid?￡?hydroxylamine (KAHA) ligations

Article abstract of DOI:10.1002/hlca.201200484

A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of β³-oligopeptides via α-keto acidi?￡?hydroxylamine (KAHA) ligation is presented. This one-pot synthetic method utilizes in situ generated nitrones bearing gulose-derived chiral auxiliaries for the asymmetric 1,3-dipolar cycloaddition with methyl 2-methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers bearing diverse side chains (proteinogenic and non-proteinogenic) can be synthesized in either configuration (like- and unlike-configured). The scalable and enantioselective synthesis of the isoxazolidine monomers enables the use of the synthesis of β³-oligopeptides via iterative α-keto acidi?￡?hydroxylamine (KAHA) ligation. Copyright

Full text of DOI:10.1002/hlca.201200484

Helvetica Chimica Acta – Vol. 95 (2012)
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Synthesis of Enantiomerically Pure Isoxazolidine Monomers for the
Preparation of b3-Oligopeptides by Iterative a-Keto AcidꢀHydroxylamine
(KAHA) Ligations
by Ying-Ling Chianga)b), Justin A. Russakc), Nancy Carrilloa), and Jeffrey W. Bode*b)
a) Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania,
Philadelphia, PA 19104, USA
b) Laboratorium fꢀr Organische Chemie, Departement fꢀr Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, Hçnggerberg HCI, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich
(phone: þ 41-44-633-2103; fax: þ 41-44-633-1235; e-mail: bode@org.chem.ethz.ch)
c) Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara,
CA 93106, USA
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
A versatile method for the synthesis of enantiomerically pure isoxazolidine monomers for the synthesis of
b3-oligopeptides via a-keto acidꢀhydroxylamine (KAHA) ligation is presented. This one-pot synthetic method
utilizes in situ generated nitrones bearing gulose-derived chiral auxiliaries for the asymmetric 1,3-dipolar
cycloaddition with methyl 2-methoxyacrylate. The resulting enantiomerically pure isoxazolidine monomers
bearing diverse side chains (proteinogenic and non-proteinogenic) can be synthesized in either configuration
(like- and unlike-configured). The scalable and enantioselective synthesis of the isoxazolidine monomers
enables the use of the synthesis of b3-oligopeptides via iterative a-keto acidꢀhydroxylamine (KAHA) ligation.
Introduction. – Peptides comprised of b-amino acids have attracted substantial
interest for their synthesis, analysis, and application [1]. The advantages of b-peptides
as functional mimics of natural peptides and therapeutic candidates derive from their
resistance to peptidases [2] and their ability to form predictable structures, such as
secondary structures [3 – 5], tertiary structures in the case of chimeric a/b-peptides [6],
and quaternary structures [7]. Several biomedical applications of b-peptides have been
studied, including antibacterial activity [8], cell penetration [9], inhibitors of
proteinꢀprotein interaction [10][11], and inhibitors of virusꢀcell fusion [12]. Despite
the potential biological activities of b-peptides, there are several synthetic limitations
that hamper the development of b-peptide peptidomimetics. For example, the
constituent monomers, b-amino acids, must be prepared from corresponding enentio-
merically pure protected a-amino acids by ArndtꢀEistert homologation [13]. While this
is largely effective for most proteinogenic amino acids [13][14], which are now widely
available at reasonable cost1), it restricts access to non-proteinogenic examples2). In
Fmoc-b3hGly-, Ala-, Val-, Leu-, Ile-, Met-, Phe-, Trp, and Pro-OH without side-chain protection,
1
)
t
Fmoc-b3hSer-, Thr-, Asp-, Glu-, and Tyr-OH with Bu protection, Fmoc-b3hLys-OH with Boc
protection, Fmoc-b3hArg-OH with Pmc protection, and Fmoc b3hAsn- and Gln-OH with trityl
protection are commercially available. Fmoc-b3hCys and His are not commercially available.
The examples of non-proteinogenic b-amino acids, including b3-homoornithine (b3-hOrn-OH) and
b3-homohomophenylalanine (b3-hHop-OH), were shown in [15].
2
)
ꢁ 2012 Verlag Helvetica Chimica Acta AG, Zꢀrich

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addition, although the synthesis of b-peptides by standard amide coupling is reliable
[16], it is hampered by sluggish reactivity and the use of super-stoichiometric amounts
of coupling reagents. The result is a generation of large amounts of waste and
contributes to the high cost of synthesizing b-oligopeptides.
We have recently identified the a-keto acidꢀhydroxylamine (KAHA) ligation as an
alternative amide-forming reaction that proceeds in the presence of unprotected
functional groups and under aqueous conditions [17]. Our primary application to date
has been the convergent ligation of unprotected peptide fragments or the cyclization of
unprotected linear peptides [18], but we have also considered the utility of this reaction
for iterative peptide synthesis. The advantages of this reaction, which do not require
coupling reagents or side-chain protecting groups, must be weighed against the
requirement of preparing the enantiomerically pure amino acid monomers. In the case
of peptides comprised of proteinogenic a-amino acids, it is currently difficult to imagine
how the need to prepare each individual monomer could offset the benefits of the
KAHA amide formation. For unnatural peptides, for which the constituent monomers
must be synthesized prior to assembly, the de novo preparation of enantiomerically
pure monomers suitable for direct, coupling reagent-free coupling offers an appealing
alternative. With these parameters in mind, we have recently demonstrated that the
KAHA ligation can be used to assemble b3-oligopeptides by iterative couplings of
enantiomerically pure isoxazolidine monomers (Scheme 1) [19]. The amide formation
between a-ketoacid and chiral isoxazolidine acetals results in NꢀO bond cleavage and
regeneration of the a-keto ester. Following hydrolysis of a-keto ester provides the a-
keto acid, which is ready for further peptide elongation. This amidation reaction
proceeds in H2O, without the need for coupling reagents or side-chain protecting
groups, and without affording any non-volatile by-products. These advantages have the
Scheme 1. Iterative, Aqueous Synthesis of b3-Oligopeptides via a-Keto AcidꢀHydroxylamine Ligation

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potential to improve the synthesis of b3-oligopeptides by avoiding issue of reactivity,
solubility, and purification that hamper the traditional b-peptide synthesis.
A postulated mechanism for the decarboxylative condensation of a-keto acids and
isoxazolidine acetals is shown in Scheme 2. Nucleophilic attack onto the a-ketone,
followed by proton transfer, renders a hemianimal intermediate. Decarboxylation
initiates a cascade of steps resulting in NꢀO bond cleavage, expelling MeOH and CO2
as by-products. Tautomerization of enol intermediate gives rise to amide formation and
formation of an a-keto ester.
Scheme 2. Postulated Mechanism for Amide Formation between a-Keto Acids and Isoxazolidine
Monomers
The key to the widespread use of this synthetic method is the versatile and facile
preparation of isoxazolidine monomers in eantiomerically pure forms. In addition, a
broader scope of side-chain functionality, acquisition of both like- and unlike-
configured monomers3), as well as increasing the ease of availability of starting
material are also needed. In this report, we document our development of a general,
reliable synthesis of both enantiomers of the isoxazolidine monomers bearing a broad
scope of side chains.
Preparation of Enantiomerically Pure Isoxazolidine Monomers. – The study of
chiral auxiliaries for the preparation of enantiomerically enriched isoxazolidines is a
rich and long-studied area of organic asymmetric synthesis. Vasella introduced a chiral
auxiliary derived from (þ)-d-mannose for the diastereoselective 1,3-dipolar cyclo-
addition reactions between chiral nitrones and a,b-unsaturated esters [21]. Our early
work took advantage of Vasellaꢂs procedure to obtain a few enantiomerically pure
isoxazolidine monomers [19][22]. Cycloadditions proceeded by refluxing a mixture
of d-mannose-derived oxime, acrylate, and the corresponding aldehyde with a
DeanꢀStark trap in one pot. The d-mannose-derived oxime formed a nitrone in situ
which underwent a 1,3-dipolar cycloaddition with the acrylate to form the isoxazolidine
monomers with ca. 9 :1 diastereoselectivity at the b-C-atom (Scheme 3).
3
)
The stereochemical convention like/unlike was proposed in [20].

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Scheme 3. General Approach to the Synthesis of Enantiomerically Pure Isoxazolidine Synthesis via One-
Pot Nitrone Cycloaddition with d-Mannose Oxime
Although the synthesis of isozaxolidines was reliable, the d-mannose-derived
auxiliary afforded the absolute configuration to the unlike-b3-amino acids after ligation
with a-keto acids, and the corresponding l-mannose is prohibitively expensive for use
as a chiral auxiliary. Furthermore, in many cases the diastereoselectivites were lower,
and the isoxazoline products were difficult to obtain as single stereoisomers by
crystallization. We turned to the report of Kibayashi and co-workers about chiral
auxiliaries derived from d-gulose and l-gulose as a convenient surrogate for mannose
to synthesize (þ)-negamycin and its epimer (ꢀ)-epinegamycin [23]. Both of d- and l-
gulose are available at a reasonable price in the form of the gulonic acid-1,4-lactone4).
More recently, we have developed and improved scalable synthesis of acetonide-
protected d-gulose- and l-gulose-derived oximes [24 – 26]. We employed the aceto-
nide-protected d-gulose- and l-gulose-derived oxime5) to synthesize like- and unlike-
configured isoxazolidines, respectively, by the 1,3-dipolar cycloaddition (Scheme 4).
These oximes not only show high selectivity but also enable easy handling as solids, and
facile chromatography and recrystallization of the diastereoisomers.
Several enantiomerically pure isoxazolidine monomers 5a – 5d, 5f, 5k, and 5l,
containing common proteinogenic side chains, such as alanine, valine, leucine,
phenylalanine, glutamate, tryptophan, and serine, respectively, have been readily
synthesized by the two-step approach. By employing appropriate aldehyde, we can also
obtain isoxazolidine monomers containing the non-proteinogenic side chain, such as 5g,
5i, and 5m. The structures and synthetic yields of like-configured (Scheme 5) and
unlike-configured (Scheme 6) monomers are shown.
4
)
)
d- and l-Gulono lactones are derived from d-xylose and l-ascorbic acid, respectively. They are
available from Carbosynth.
d- and l-Gulose oxime chiral auxiliaries are now commercially available from BioBlocks, Inc.
5

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Scheme 4. Diastereoselective Synthesis of like- and unlike-Isoxazolidine Monomers Controlled by d-
Gulose- and l-Gulose-Derived Oxime, Respectively
When attempting to synthesize monomers possessing nucleophilic N-atoms, such as
lysine (5h), ornithine (5g), and arginine monomers (5j), we encountered a problematic
self-condensation of nitrones by the side chain. For example, aldehyde 9 was
synthesized as a suitable substrate for the one-pot synthesis to give the lysine
monomer. Once nitrone 10 was formed, the amine was able to attack the nitrone
functionality yielding 11, rendering it useless for formation of the desired monomer
(Scheme 7).
We considered several strategies to avoid the self-condensation of nitrones
possessing N-atoms. First, a bis-protected amino aldehyde 12 was used in the synthesis
of ornithine monomer 5g. Bis-protected monomer 4g-1 was obtained in 53% isolated
yield as the major diastereoisomer after chromatography and recrystallization. After

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Scheme 7. Intramolecular Cyclization with Nucleophilic Side Chains
removal of the Cbz (¼(benzyloxy)carbonyl) group by hydrogenation, a Boc-protected
ornithine monomer 4g was obtained (Scheme 8).
Scheme 8. Synthesis of Isoxazolidine Monomers 5g Bearing Ornithine Side Chain
Alternatively, an azido aldehyde 13 can be used for the synthesis of lysine monomer
5h. When an azide functionality was replaced with the protected amine (aldehyde 13),
no products similar to 11 were observed. Azide monomer 4h-1 was obtained in 31%
isolated yield as the major diastereoisomer after chromatography and recrystallization.
This required only one step to arrive at the sugar protected lysine monomer 4h;
reduction of the azide by hydrogenation and Boc protection (Scheme 9) in a one-pot
reaction.
The synthesis of arginine monomer 5j can be achieved from the azido monomers 4j-
2. To arrive at the sugar-protected bis-Boc-arginine isoxazolidine, simple use of the
guanidino aldehyde resulted in very low yields presumably due to self-condensation of
the generated nitrone. We used a Bz (¼ benzoyl)-protected alcohol that could serve as a
modifiable functional group after cycloaddition. Aldehyde 14 was found to be suitable
to give non-proteinogenic isoxazolidine 4i in 48% yield. The Bz group was easily

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Scheme 9. Synthesis of Isoxazolidine Monomers 5h Bearing Lysine Side Chain
removed after the cycloaddition with MeONa, a reagent that did neither deprotect the
sugar auxiliary nor disturb the integrity of the methyl ester functionality on the
isoxazolidine ring, to afford free alcohol 4j-1 in 92% yield. Compound 4j-1 was
converted to an azide with diphenylphosphoryl azide by Mitsunobu reaction in 84%
yield. In a one-pot, two-step procedure, azide 4j-2 was reduced with Ph3P and coupled
with N,N’-bis[(tert-butoxy)carbonyl]-S-methylisothiourea (15) to give the sugar-
protected bis-Boc arginine isoxazolidine monomer 4j in 48% yield (Scheme 10).
The isoxazolidine monomer bearing aspartic acid side chain, 5n, proved syntheti-
cally challenging and demanded an alternative route to its preparation. By using the
established protocol for unlike-configured isoxazolidine monomer containing aspartic
acid side chain with d-mannose-derived oxime [22], the synthesis of the like-configured
monomer 5n was achieved with d-gulose-derived oximes (Scheme 11). b-Sulfanyl
aldehyde 16 proved to be a good surrogate of g-protected formyl-ester and suitable for
the use in the chiral auxiliary-directed cycloaddition. The cycoadduct 4n-1 can be
obtained as a single diastereoisomer. Oxidation to the sulfoxide 4n-2, followed by
Pummerer oxidation, rendered the aldehyde 4n-3 in high yield. Subsequent Pinnick
oxidation afforded the carboxylic acid 4n-4 in excellent yield. The free acid side chain
t
was protected with Bu group to afford ester 4n-5 for the purification purpose.
Deprotection and Recycling of the Chiral Auxiliary. – Several deprotection
methods of carbohydrate-derived auxiliaries have been reported in the literature, such
as with HCOOH [27], HCl [28], TsOH [29], or HClO4 [30]. Early studies in our group
showed that 2 – 3 equiv. of HClO4 in MeOH served to deprotect the isoxazolidines
cleanly and in good-to-high yields [19]. Hydrolysis of the sugar moiety allows for
biphasic extraction to give relatively pure isoxazolidine in the organic layer, however,
chromatography is still necessary. Although some epimerization occurs at the acetal,

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Scheme 10. Synthesis of Isoxazolidine Monomers 5j Bearing Arginine Side Chain
this is inconsequential, because the major diastereoisomer has already been isolated at
this point, and the stereogenic center of acetal is lost in the subsequent ligation step.
The procedure of acid hydrolysis works well when used in most cases where the amino
acid side chain bears purely aliphatic or aromatic functionality. For acid-sensitive
groups, alternative methods needed to be explored.
A milder deprotection method using hydroxylamine was adapted from work done
by Wittenberger and co-workers [31], and later by Carreira and co-workers [32].
NH2OH · HCl buffered with AcONa in aqueous MeOH provided the N-unsubstituted
isoxazolidine and the gulose-derived oxime in good yields. This procedure was proved
to be a good alternative cleavage method for the most isoxazolidine monomers bearing
t
acid-sensitive group, such as Bu- or Boc-protected side chains. A major advantage of
NH2OH-mediated cleavage is that the chiral auxiliary can be recovered and reused.
Some substrates, however, did not survive well under the two conditions mentioned
above, in particular, primary amine or alcohol with Boc protecting groups. Carreira and
co-workers reported NH2NH2 · 2 HCl buffered with AcONa can be another choice
[32], albeit no recovery or recycling of the auxiliary was attempted. This cleavage
method worked well to preserve Boc-protected side chains, such as ornithine, lysine,
and serine, of the isoxazolidine monomers 5g, 5h, and 5l, respectively.
With the arginine isoxazolidine monomer, none of the three methods mentioned
above were successful. Removal of the auxiliary of 4j using the NH2OH · HCl method

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Scheme 11. Synthesis of Isoxazolidine Monomers 5n Bearing Aspartic Acid Side Chain
or NH2NH2 · 2 HCl method led to hydrolysis of the guanidine group, actually giving a
b3-ornithine monomer instead. Interestingly, HClO4 deprotection in MeCN proceeded
first with deprotection of the auxiliary, so the reaction could be monitored and stopped
to obtain the di-Boc-protected 5j isoxazolidine monomer. The cleavage methods of
chiral auxiliary are compiled in the Table.
Conclusions and Outlook. – We have developed and optimized the synthesis of
isoxazolidine monomers as part of a larger program to establish the a-keto acid-
hydroxylamine (KAHA) ligation as an alternative to traditional, coupling-reagent
based approaches to b3-oligopeptide synthesis. The production of these isoxazolidine
monomers can be achieved on a reasonable scale and with good yields. We have
optimized the synthesis of starting material, such as d-gulose- and l-gulose-derived
oximes [26], and suitable aldehydes, so isoxazolidine monomers can be synthesized in a
reasonable cost. In addition, the KAHA ligation proceeds in aqueous solution, requires
no reagents or catalysts, and produces only MeOH and CO2 as by-products. All of these
advantages render our methodology more economic and environmentally friendly
compared to the traditional approaches to b3-oligopeptide synthesis.
Experimental Part
1. General. Abbreviations: Bn: benzyl, Boc: tert-butoxycarbonyl, Boc2O: di(tert-butyl) dicarbonate,
Bz: benzoyl, Cbz: (benzyloxy)carbonyl, DEAD: diethyl azodicarboxylate, DPPA: diphenylphosphoryl
azide, mCPBA: meta-chloroperoxybenzoic acid, TFAA: trifluoroacetic anhydride, (CF3CO)2O.

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Table. Available Methods for Deprotection of Chiral Auxiliary
Cleavage procedure
Reagents
Recovers
of gulose
oxime
Applicable isoxazolidine
GP B1
GP B2
GP B3
GP B4
HClO4, MeOH, 658
no
yes
no
no
Aliphatic or aromatic
side chain: 5a – 5e, 8a – 8d
Acid-sensitive side chain:
5f, 5i, 5k, 5m, 8e – 8g
Acid-sensitive side chaina):
5g, 5h, 5l, 5n
NH2OH · HCl, AcONa,
MeOH/H2O 3 : 1, 658
NH2NH2 · 2 HCl, AcONa,
MeOH/H2O 3 : 1, 658
HClO4, MeCN, r.t.
Argb) (5j)
a) In particular, primary amine or alcohol with Boc protecting groups. b) This procedure could also be
applied to most isoxazolidines with aliphatic or aromatic side chains.
All reactions utilizing air- or moisture-sensitive reagents were performed in dried glassware under
dry N2. CH2Cl2 were distilled from CaH2. THF was distilled from Na. N,N-Diisopropylethylamine
(EtNiPr2) were distilled from KOH. TLC: EMD precoated plates (silica gel 60 F254, Art 5715, 0.25 mm);
visualization by fluorescence quenching under UV and by staining with phosphomolybdic acid or
KMnO4. Prep. thin-layer chromatography (PTLC): plates prepared from EMD silica gel 60 PF254
(Art. 7749). Column chromatography (CC): EMD silica gel 60 (230 – 400 mesh) using a forced flow of
0.5 – 1.0 bar. Optical rotations: Jasco DIP-1000 polarimeter operating at the sodium D-line with a 100-
mm path length cell; as [a]TD (concentration (g/100 ml), solvent). IR Spectra: Jasco FT/IR-4100
1
spectrophotometer as a thin film; in cmꢀ1. H- (500 MHz) and 13C-NMR (125 MHz): Bruker Avance
AVII-500 spectrometer; 1H- (400 MHz) and 13C-NMR (100 MHz): Varian Unity 400 spectrometer in
CDCl3; chemical shifts in ppm downfield from residual of protonated deuterium solvent peaks for
1H-NMR and deuterium solvent peaks for 13C-NMR, coupling constants J in Hz.
2. General Procedures A, B1, B2, B3, and B4. General Procedure A (GP A): Nitrone Cycloadditions
with the Gulose-Derived Chiral Auxiliary. A 0.3m soln. of d-gulose oxime or l-gulose oxime (32.6 mmol,
1.00 equiv.), aldehyde (1.00 – 1.50 equiv.), and methyl 2-methoxyacrylate (2.50 – 5.00 equiv.) in toluene
(0.3m) was heated to reflux and stirred in a round-bottom flask with a DeanꢀStark trap fitted with a reflux
condenser. The reaction was monitored by TLC until the absence of a UV-active nitrone spot. After
cooling to r.t., the solvent was concentrated under reduced pressure. The crude product was purified by
flash chromatography (FC) with the following conditions: 1) The column was packed with hexanes/
AcOEt 9 :1 and the crude mixture loaded with a minimal amount of toluene. 2) The excess methyl 2-
methoxyacrylate (3) was eluted with the same solvent mixture as was packed with (monitored by TLC,
UV-active spot Rf 0.7 in hexanes/AcOEt 9 :1). 3) Fractions were collected eluting all four possible
diastereoisomers (Note: the diastereoisomers with the highest Rf and the lowest Rf are always the
undesired diastereoisomers, the middle two diastereoisomers are always the desired diastereoisomers.
The separation on the column should be so that most of the undesired diastereoisomers are not present in
the collected fractions). 4) The collected fractions of the desired diastereoisomers were combined, the
solvent was evaporated and further dried under vacuum. The crude solid (or sometimes thick oil) was
recrystallized from heptanes (50 ml/g) to give a single diastereoisomer.

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General Procedure B1 (GP B1): Auxillary Cleavage with HClO4 in MeOH. To a 0.1m soln. of the
gulose-isoxazolidine (5.27 mmol, 1.00 equiv.) in MeOH was slowly added HClO4 (70% (w/w),
10.6 mmol, 2.00 equiv.) and refluxed for 4 h. After cooling to r.t., the reaction was quenched by the
addition of a sat. Na2CO3 soln., and the mixture was extracted with AcOEt (3ꢁ). The org. layers were
combined, washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The
resulting residue was purified by FC.
General Procedure B2 (GP B2): Auxiliary Cleavage with NH2OH · HCl. To a 0.1m soln. of the gulose-
isoxazolidine (2.28 mmol, 1.00 equiv.) in MeOH/H2O 3 :1 was added NH2OH · HCl (9.60 equiv.) and
AcONa (9.00 equiv.) in one portion and heated at 658 for 12 h. Another portion of NH2OH · HCl and
AcONa was added until starting material was consumed (TLC). The mixture was cooled to r.t. and
further cooled in an ice bath. The reaction was quenched with sat. aq. NaHCO3, and the mixture was
extracted with AcOEt (3ꢁ). The org. layers were combined, washed with brine, dried (Na2SO4), filtered,
and concentrated under reduced pressure. The resulting residue was purified by FC to the afford the N-
unsubstituted isoxazolidine and the gulose oxime.
General Procedure B3 (GP B3): Auxiliary Cleavage with NH2NH2 · 2 HCl. To a 0.10m soln. of the
gulose-isoxazolidine (9.90 mmol, 1.00 equiv.) in MeOH/H2O (3 :1) was added NH2NH2 · 2 HCl
(9.00 equiv.) and AcONa (8.60 equiv.). The mixture was stirred at 608 for 9 h, then treated with ice,
neutralized with NaHCO3, and extracted with AcOEt (3ꢁ). The org. layers were separated, washed with
brine, dried (NaSO4), filtered, and concentrated in vacuo. The resulting material was purified by FC to
afford the N-unsubstituted isoxazolidine.
General Procedure B4 (GP B4): Auxillary Cleavage with HClO4 in MeCN. To a 0.1m soln. of the
gulose-isoxazolidine (0.05 mmol, 1.00 equiv.) in MeCN was slowly added HClO4 (70% (w/w),
0.125 mmol, 2.50 equiv.) and stirred for 2 h. The reaction was quenched by the addition of a sat.
NaHCO3 soln., and the mixture was extracted with AcOEt (3ꢁ). The org. layers were combined, washed
with brine, dried (Na2SO4O), filtered, and concentrated under reduced pressure. The resulting residue
was purified by FC.
3. Preparation of Isoxazolidine Monomers. 3.1. Preparation of Enantiomerically Pure Isoxazolidine
Monomers with like-Configured Residues (Scheme 5). Methyl (3S,5R)-N-(2,3 :5,6-Di-O-isopropylidene-
b-d-gulofuranosyl)-5-methoxy-3-methylisoxazolidine-5-carboxylate (4a). Prepared according to GP A.
Yield: 54%. White crystalline solid. M.p. 1058. [a]2D0 ¼ þ28.3 (c ¼ 1.00, CHCl3). IR: 2991, 2939, 1748,
1452, 1374, 1270, 1227, 1069, 852. 1H-NMR (400 MHz): 5.00 (d, J ¼ 6.0, 1 H); 4.70 (dd, J ¼ 6.0, 4.0, 1 H);
4.67 (s, 1 H); 4.39 – 4.33 (m, 1 H); 4.19 (dd, J ¼ 8.8, 6.8, 1 H); 4.10 (dd, J ¼ 8.4, 3.6, 1 H); 3.80 (s, 3 H);
3.72 (dd, J ¼ 8.8, 6.8, 1 H); 3.53 – 3.48 (m, 1 H); 3.36 (s, 3 H); 2.72 (dd, J ¼ 13.2, 7.6, 1 H); 2.19 (dd, J ¼
13.6, 6.0, 1 H); 1.46 (s, 3 H); 1.40 (s, 3 H); 1.37 (s, 3 H); 1.31 (d, J ¼ 6.4, 3 H); 1.30 (s, 3 H). 13C-NMR
(100 MHz): 169.2; 112.9; 109.9; 105.2; 98.9; 84.4; 84.0; 80.5; 75.9; 66.2; 58.8; 53.1; 52.1; 47.2; 27.0; 26.3;
25.6; 25.1; 19.1. HR-ESI-MS: 440.1892 ([M þ Na]þ, C19H31NO9þ ; calc. 440.1891).
Methyl (3S,5R)-5-Methoxy-3-methylisoxazolidine-5-carboxylate (5a). Prepared according to GP B1.
Yield: 90%. Clear oil. [a]2D0 ¼ þ78.5 (c ¼ 1.00, CHCl3). IR: 3214, 2955, 2838, 1749, 1438, 1069. 1H-NMR
(400 MHz): 5.46 (s, 1 H); 3.78 (s, 3 H); 3.56 – 3.46 (m, 1 H); 3.29 (s, 3 H); 2.64 (dd, J ¼ 13.2, 8.4, 1 H);
1.91 (dd, J ¼ 13.2, 8.0, 1 H); 1.20 (d, J ¼ 6.4, 3 H). 13C-NMR (100 MHz): 168.5; 108.6; 56.3; 52.9; 52.0;
49.5; 16.2. HR-ESI-MS: 198.0750 ([M þ Na]þ, C7H13NNaO4þ ; calc. 198.0742).
Methyl (3R,5R)-N-(2,3 :5,6-Di-O-isopropylidene-b-d-gulofuranosyl)-3-isopropyl-5-methoxyisoxa-
zolidine-5-carboxylate (4b). Prepared according to GP A. Yield: 55%. White crystalline solid. M.p.
114 – 1168. [a]2D0 ¼ þ7.8 (c ¼ 1.00, CHCl3). IR: 2983, 2873, 1751, 1455, 1371, 1210, 1068, 895, 733. 1H-NMR
(400 MHz): 5.04 (d, J ¼ 6.0, 1 H); 4.71 (dd, J ¼ 6.0, 4.0, 1 H); 4.65 (s, 1 H); 4.39 – 4.33 (m, 1 H); 4.21 (dd,
J ¼ 8.4, 6.8, 1 H); 4.12 (dd, J ¼ 8.4, 4.0, 1 H); 3.82 (s, 3 H); 3.74 (dd, J ¼ 8.4, 6.4, 1 H); 3.33 (s, 3 H);
3.28 – 3.23 (m, 1 H); 2.54 – 2.42 (m, 2 H); 2.01 – 1.92 (m, 1 H); 1.46 (s, 3 H); 1.40 (s, 3 H); 1.38 (s, 3 H);
1.31 (s, 3 H); 0.96 (d, J ¼ 6.4, 3 H); 0.90 (d, J ¼ 6.8, 3 H). 13C-NMR (100 MHz): 170.0; 112.8; 110.0;
106.9; 97.9; 84.5; 84.2; 80.5; 75.9; 68.1; 66.2; 53.2; 52.2; 40.6; 29.7; 26.8; 26.3; 25.5; 25.2; 21.4; 19.3. HR-
ESI-MS: 468.2225 ([M þ Na]þ, C21H35NNaO9þ ; calc. 468.2204).
Methyl (3R,5R)-3-Isopropyl-5-methoxyisoxazolidine-5-carboxylate (5b). Prepared according to
GP B1. Yield: 94%. Clear oil. [a]2D0 ¼ þ101.8 (c ¼ 1.00, CHCl3). IR: 3213, 2959, 1752, 1466, 1438, 1267,
1219, 1070, 1047. 1H-NMR (400 MHz): 5.61 (br. s, 1 H); 3.78 (s, 3 H); 3.29 (s, 3 H); 3.23 – 3.10 (m, 1 H);

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Helvetica Chimica Acta – Vol. 95 (2012)
2.54 (dd, J ¼ 8.3, 13.4, 1 H); 2.06 – 1.96 (m, 1 H); 1.72 – 1.61 (m, 1 H); 0.96 (d, J ¼ 6.8, 1 H); 0.90 (d, J ¼
6.4, 1 H). 13C-NMR (100 MHz): 168.8; 108.53; 67.6; 53.2; 52.2; 51.9; 46.8; 45.4; 30.9; 21.1; 20.4. HR-ESI-
MS: 204.1230 ([M þ Na]þ, C9H17NNaOþ4 ; calc. 204.1230).
Methyl (3S,5R)-N-(2,3 :5,6-Di-O-isopropylidene-b-d-gulofuranosyl)-5-methoxy-3-(2-methylpropyl)-
isoxazolidine-5-carboxylate (4c). Prepared according to GP A. Yield: 47%. White crystalline solid. M.p.
122 – 1238. [a]2D0 ¼ þ10.4 (c ¼ 1.00, CHCl3). IR: 2986, 254, 1755, 1449, 1380, 1275, 1221, 1092, 872, 721,
598. 1H-NMR (400 MHz): 5.04 (d, J ¼ 6.0, 1 H); 4.70 (dd, J ¼ 6.0, 3.6, 1 H); 4.66 (s, 1 H); 4.40 – 4.35 (m,
1 H); 4.21 (dd, J ¼ 8.4, 6.8, 1 H); 4.08 (dd, J ¼ 8.4, 4.0, 1 H); 3.82 (s, 3 H); 3.73 – 3.69 (m, 1 H); 3.37 (s,
3 H); 2.70 (dd, J ¼ 13.6, 8.0, 1 H); 2.19 (dd, J ¼ 13.6, 2.8, 1 H); 1.85 – 1.78 (m, 1 H); 1.70 – 1.60 (m, 1 H);
1.46 (s, 3 H); 1.41 (s, 3 H); 1.37 (s, 3 H); 1.31 (s, 3 H); 1.24 – 1.17 (m, 1 H); 0.92 (dd, J ¼ 6.4, 5.6, 6 H).
13C-NMR (100 MHz): 169.6; 112.9; 109.9; 107.2; 97.9; 84.5; 84.3; 80.5; 75.8; 66.2; 60.0; 53.2; 52.3; 44.8;
42.9; 26.8; 26.3; 25.9; 25.4; 25.2; 23.3; 22.2. HR-ESI-MS: 482.2342 ([M þ Na]þ, C22H37NNaO9þ ; calc.
482.2360).
Methyl (3S,5R)-5-Methoxy-3-(2-methylpropyl)isoxazolidine-5-carboxylate (5c). Prepared according
to GP B1. Yield: 87%. Colorless oil. [a]2D0 ¼ þ93.3 (c ¼ 1.00, CHCl3). IR: 3215, 2955, 2872, 2842, 1752,
1
1439, 1387, 1267, 1070, 810. H-NMR (400 MHz)6): 6.15 (s, 1 H*); 5.46 (s, 1 H#); 3.79 (s, 3 H#); 3.77 (s,
3 H*); 3.59 – 3.52 (m, 1 H*); 3.52 – 3.42 (m, 1 H#); 3.30 (s, 3 H#); 3.27 (s, 3 H*); 2.62 (dd, J ¼ 13.2, 8.0,
1 H#); 2.50 (dd, J ¼ 13.2, 7.2, 1 H*); 2.04 (m, 1 H*); 1.91 (m, 1 H#); 1.68 – 1.58 (m, 1 H#); 1.48 – 1.42 (m,
1 H#); 1.37 – 1.30 (m, 1 H#); 0.89 (dd, J ¼ 10, 6.4, 6 H#). 13C-NMR (100 MHz): 168.6; 108.2; 59.4; 53.0;
52.9; 52.0; 51.9; 48.6; 47.9; 40.7; 26.7; 23.0; 22.9; 22.8. HR-ESI-MS: 240.1212 ([M þ Na]þ, C10H19NNaO4þ ;
calc. 240.1206).
Methyl (3S,5R)-3-Benzyl-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulofuranosyl)-5-methoxyisoxazoli-
dine-5-carboxylate (4d). Prepared according to GP A. Yield: 57%. White crystalline solid. M.p. 1218.
[a]2D0 ¼ ꢀ19.1 (c ¼ 1.00, CHCl3). IR: 3217, 3027, 2951, 1749, 1454, 1438, 1067. 1H-NMR (400 MHz): 7.30 –
7.18 (m, 5 H); 5.02 (d, J ¼ 6.0, 1 H); 4.71 (s, 1 H); 4.66 (dd, J ¼ 5.6, 4.0, 1 H); 4.35 – 4.30 (m, 1 H); 4.16
(dd, J ¼ 8.4, 6.8, 1 H); 3.90 – 3.81 (m, 1 H); 3.80 (s, 3 H); 3.62 (dd, J ¼ 8.4, 6.8, 1 H); 3.43 (s, 3 H); 3.12
(dd, J ¼ 13.6, 6.8, 1 H); 2.83 (dd, J ¼ 13.6, 8.8, 1 H); 2.51 (dd, J ¼ 13.6, 8.0, 1 H); 2.32 (dd, J ¼ 14.0, 3.2,
1 H); 1.45 (s, 3 H); 1.42 (s, 3 H); 1.37 (s, 3 H); 1.31 (s, 3 H). 13C-NMR (100 MHz): 169.5; 138.8; 129.7;
128.6; 126.5; 112.9; 109.9; 106.6; 97.8; 84.4; 84.2; 80.4; 75.8; 66.2; 63.0; 53.2; 52.2; 43.5; 39.9; 27.1; 26.3;
25.6; 25.1. HR-ESI-MS: 516.2216 ([M þ Na]þ, C25H35NNaO9þ ; calc. 516.2204).
Methyl (3S,5R)-3-Benzyl-5-methoxyisoxazolidine-5-carboxylate (5d). Prepared according to GP B1.
Yield: 88%. Clear oil. [a]2D0 ¼ þ90.1 (c ¼ 1.00, CHCl3). IR: 3214, 3028, 2952, 1750, 1497, 1439, 1310, 1209,
1067, 702. 1H-NMR (400 MHz)6): 7.31 – 7.18 (m, 5 H#); 6.21 (s, 1 H*); 5.68 (s, 1 H#); 3.78 (s, 3 H#); 3.78 (s,
3 H*); 3.34 (s, 3 H#); 3.33 (s, 3 H*); 3.04 (dd, J ¼ 13.6, 5.6, 1 H#); 3.03 – 2.98 (m, 1 H*); 2.79 – 2.71 (m,
1 H*); 2.72 – 2.67 (m, 1 H#); 2.55 – 2.48 (m, 1 H#); 2.47 – 2.42 (m, 1 H*); 2.26 (m, 1 H*); 2.10 (m, 1 H#).
13C-NMR (100 MHz): 168.5; 137.7; 129.5; 129.1; 128.9; 128.7; 126.9; 126.7; 108.3; 107.9; 62.0; 61.1; 53.1;
53.0; 52.1; 51.9; 47.4; 47.0; 37.6. HR-ESI-MS: 247.1050 ([M þ Na]þ, C13H17NNaO4þ ; calc. 274.1049).
Methyl (3R,5R)-N-(2,3 :5,6-Di-O-isopropylidene-b-d-gulofuranosyl)-5-methoxy-3-phenylisoxazoli-
dine-5-carboxylate (4e). Prepared according to GP A. Yield: 32%. White crystalline solid. M.p. 110 –
1138. [a]2D0 ¼ þ47.8 (c ¼ 1.00, CHCl3). IR: 3062, 2986, 2938, 1753, 1496, 1455, 1381, 1211, 1089, 1068,
891, 850, 701. 1H-NMR (400 MHz): 7.45 – 7.38 (m, 2 H); 7.32 – 7.21 (m, 3 H); 5.08 (d, J ¼ 6.4, 1 H); 4.75 (s,
1 H); 4.67 (dd, J ¼ 6.0, 4.0, 1 H); 4.39 (t, J ¼ 8.4, 1 H); 4.23 (dd, J ¼ 14.8, 6.8, 1 H); 4.11 (dd, J ¼ 8.4, 6.8,
1 H); 3.83 (s, 3 H); 3.86 – 3.80 (m, 1 H); 3.58 (dd, J ¼ 8.4, 7.2, 1 H); 3.40 (s, 3 H); 2.98 (dd, J ¼ 12513.6,
8.4, 1 H); 2.58 (dd, J ¼ 13.6, 7.6, 1 H); 1.42 (s, 3 H); 1.31 (s, 3 H); 1.29 (s, 3 H); 1.26 (s, 3 H). 13C-NMR
(100 MHz): 168.9; 138.7; 128.8; 128.1; 127.8; 112.9; 109.8; 104.7; 98.5; 84.6; 82.8; 80.8; 76.0; 66.8; 66.1;
53.2; 52.0; 48.9; 26.9; 26.3; 25.5; 25.0. HR-ESI-MS: 502.2064 ([M þ Na]þ, C24H33NNaO9þ ; calc. 502.2047).
Methyl (3R,5R)-5-Methoxy-3-phenylisoxazolidine-5-carboxylate (5e). Prepared according to
GP B1. Yield: 91%. Clear oil. [a]2D0 ¼ þ21.2 (c ¼ 1.00, CHCl3). IR: 2952, 1749, 1496, 1437, 1265, 1069.
1H-NMR (400 MHz)6): 7.42 – 7.25 (m, 5 H#); 5.78 (s, 1 H#); 4.66 (m, 1 H*); 4.56 (m, 1 H#); 3.85 (s, 3 H#);
3.80 (s, 3 H*); 3.40 (s, 3 H#); 2.93 (dd, J ¼ 13.2, 9.2, 1 H#); 2.54 (dd, J ¼ 13.2, 7.2, 1 H#). 13C-NMR
#: Major diastereoisomer, *: minor diastereoisomer.
6
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(100 MHz): 168.5; 137.0; 129.5; 129.0; 128.3; 108.9; 64.7; 53.4; 52.3; 49.1. HR-ESI-MS: 260.0895 ([M þ
Na]þ, C12H15NNaOþ4 ; calc. 260.0899).
Methyl (3S,5R)-3-[3-(tert-Butoxy)-3-oxopropyl]-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulofurano-
syl)-5-methoxyisoxazolidine-5-carboxylate (4f). Prepared according to GP A. Yield: 61%. Colorless
oil. [a]2D6 ¼ þ3.9 (c ¼ 0.60, CH2Cl2). IR: 2981, 2937, 1752, 1729, 1455, 1381, 1370, 1209. 1H-NMR
(400 MHz): 5.03 (d, J ¼ 6.1, 1 H); 4.72 (dd, J ¼ 6.0, 3.9, 1 H); 4.65 (s, 1 H); 4.41 – 4.36 (m, 1 H); 4.24 (dd,
J ¼ 8.5, 6.8, 1 H); 4.14 (dd, J ¼ 8.5, 3.9, 1 H); 3.84 (s, 3 H); 3.78 (dd, J ¼ 8.5, 6.8, 1 H); 3.64 – 3.59 (m, 1 H);
3.39 (s, 3 H); 2.71 (dd, J ¼ 13.5, 8.2, 1 H); 2.36 (dd, J ¼ 9.9, 5.8, 1 H); 2.29 – 2.25 (m, 2 H); 2.18 – 2.11 (m,
1 H); 1.77 – 1.71 (m, 1 H); 1.48 (s, 3 H); 1.47 (s, 3 H); 1.45 (s, 9 H); 1.41 (s, 3 H); 1.33 (s, 3 H). 13C-NMR
(100 MHz): 172.4; 169.5; 112.7; 109.8; 106.6; 97.7; 84.4; 83.9; 80.3; 80.1; 75.7; 66.0; 61.3; 53.0; 52.0; 43.9;
33.4; 28.8; 28.1; 28.1; 26.7; 26.1; 25.5; 24.9. HR-ESI-MS: 532.2751 ([M þ H]þ, C25H42NO1þ1 ; calc.
532.2752).
Methyl (3S,5R)-3-[3-(tert-Butoxy)-3-oxopropyl]-5-methoxyisoxazolidine-5-carboxylate (5f). Pre-
pared according to GP B2. Yield: 46%. Clear oil. [a]2D7 ¼ þ22.3 (c ¼ 0.37, CH2Cl2). IR: 2979, 2952, 1749,
1730, 1437, 1367. 1H-NMR (400 MHz)6): 3.85 (s, 3 H*); 3.84 (s, 3 H#); 3.57 – 3.44 (m, 1 H); 3.37 (s, 3 H#);
3.36 (s, 3 H*); 2.68 (dd, J ¼ 13.3, 8.4, 1 H#); 2.59 (dd, J ¼ 13.3, 7.7, 1 H*); 2.36 (t, J ¼ 7.5, 2 H); 2.17 (dd, J ¼
13.3, 4.4, 1 H*); 2.04 (dd, J ¼ 13.0, 7.1, 1 H#); 1.88 (m, 2 H); 1.47 (s, 9 H). 13C-NMR (100 MHz): 172.5;
172.0; 168.3; 108.0; 107.6; 80.6; 80.3; 60.3; 52.8; 52.7; 51.9; 51.6; 47.7; 33.0; 32.6; 28.1; 26.8. HR-ESI-MS:
290.1600 ([M þ H]þ, C13H24NOþ6 ; calc. 290.1598).
Methyl (3S,5R)-3-{3-[(tert-Butoxycarbonyl)amino]propyl}-N-(2,3 :5,6-di-O-isopropylidene-b-d-gu-
lofuranosyl)-5-methoxyisoxazolidine-5-carboxylate (4g). Compound 4g-1 was prepared according to
GP A (yield: 53%). Compound 4g-1 (10.0 g, 14.4 mmol) was dissolved in AcOEt/MeOH (140 ml/14 ml),
and 10% Pd/C (1.0 g) was added. The resulting black suspension was stirred vigorously under H2 for 2 h.
The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude compound
was purified by FC (hexanes/AcOEt 70 :30) to give 4g (8.0 g 99%). White crystalline solid. M.p. 93 – 958.
[a]2D0 ¼ ꢀ4.28 (c ¼ 0.27, CHCl3). IR: 3382, 2980, 2937, 1752, 1713, 1519, 1454, 1369, 1252, 1210, 1168, 1088,
1065. 1H-NMR (500 MHz): 5.02 (d, J ¼ 6.0, 1 H); 4.70 (dd, J ¼ 4.0, 6.0, 1 H); 4.68 (br., 1 H); 4.64 (s, 1 H);
4.22 (dd, J ¼ 7.0, 9.0, 1 H); 4.10 (dd, J ¼ 4.0, 8.5, 1 H); 3.81 (s, 3 H); 3.72 (dd, J ¼ 7.0, 8.5, 1 H); 3.36 (s,
3 H); 3.13 – 3.12 (m, 2 H); 2.70 (dd, J ¼ 8.0, 13.5, 1 H); 2.22 (dd, J ¼ 2.5, 13.5, 1 H); 1.89 – 1.81 (m, 1 H);
1.58 (br., 1 H); 1.52 – 1.47 (m, 2 H); 1.46 (s, 3 H); 1.43 (s, 12 H); 1.39 (s, 3 H); 1.31 (s, 3 H). 13C-NMR
(125 MHz): 169.5; 156.0; 112.9; 109.9; 106.4; 98.2; 84.5; 84.0; 80.4; 79.1; 75.9; 66.2; 62.0; 53.1; 52.2; 44.5;
40.4; 31.0; 28.6; 27.7; 26.9; 26.3; 25.5; 25.1. HR-ESI-MS: 583.2872 ([M þ Na]þ, C26H44N2NaO1þ1 ; calc.
583.2837).
Methyl (3S,5R)-3-{3-[(tert-Butoxycarbonyl)amino]propyl}-5-methoxyisoxazolidine-5-carboxylate
(5g). Prepared according to GP B3. Yield: 78%. Yellow oil. [a]2D0 ¼ þ30.9 (c ¼ 1.06, CHCl3). IR: 3392,
2976, 2936, 2868, 1752, 1710, 1522, 1454, 1391, 1366, 1269, 1252, 1172, 1070. 1H-NMR (500 MHz)6): 6.15
(br., 1 H*); 5.54 (br., 1 H#); 4.59 (br., 1 H#); 4.35 (br., 1 H*); 3.81 (s, 3 H); 3.43 (br., 1 H); 3.33 (s, 3 H);
3.12 (br., 2 H); 2.64 (dd, J ¼ 8.5, 13, 1 H#); 2.55 (dd, J ¼ 7.5, 13.5, 1 H*); 2.10 (br., 1 H*); 1.96 (br., 1 H#);
1.55 – 1.52 (m, 4 H); 1.42 (s, 9 H). 13C-NMR (125 MHz): 156.0; 108.1; 107.7; 79.3; 60.7; 52.9; 52.8; 51.9;
51.7; 48.0; 40.3; 29.8; 28.5; 28.0. HR-ESI-MS: 341.1723 ([M þ Na]þ, C14H26N2NaO6þ ; calc. 341.1683).
Methyl (3S,5R)-3-{4-[(tert-Butoxycarbonyl)amino]butyl}-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulo-
furanosyl)-5-methoxyisoxazolidine-5-carboxylate (4h). Compound 4h-1 was prepared according to GP A
(yield: 47%). Compound 4h-1 (4.4 g, 8.8 mmol) and Boc2O (2.85 g, 13.2 mmol) were dissolved in AcOEt/
MeOH (90 ml/9 ml), and 10% Pd/C (0.44 g) was added. The resulting black suspension was stirred
vigorously under H2 for 48 h. The mixture was filtered through Celite, and the filtrate was concentrated in
vacuo. The crude compound was purified via FC (hexanes/AcOEt 7:3) to give 4h (4.25 g, 84%). White
solid. M.p. 95 – 978. [a]2D4 ¼ þ8.8 (c ¼ 1.00, CHCl3). IR: 3370, 2979, 2936, 1750, 1455, 1368, 1210, 1065, 848,
774. 1H-NMR (400 MHz): 5.02 (d, J ¼ 6.0, 1 H); 4.73 – 4.65 (m, 1 H); 4.63 (s, 1 H); 4.60 – 4.50 (m, 1 H);
4.40 – 4.01 (m, 3 H); 3.81 (s, 3 H); 3.74 – 3.6 (m, 1 H); 3.40 – 3.60 (m, 1 H); 3.33 (s, 3 H); 3.15 – 3.01 (m,
2 H); 2.67 (dd, J ¼ 13.2, 4.8, 1 H); 2.15 – 2.25 (m, 1 H); 1.60 – 1.20 (m, 2 H). 13C-NMR (100 MHz): 169.5;
156.1; 112.8; 109.9; 106.3; 98.3; 84.4; 84.1; 80.5; 79.2; 75.9; 66.2; 62.2; 53.1; 52.2; 44.6; 33.3; 29.8; 28.6;
26.3; 25.5; 25.1; 24.4. HR-ESI-MS: 575.3206 ([M þ H]þ, C27H47N2O1þ1 ; calc. 575.3174).

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Methyl (3S,5R)-3-{4-[(tert-Butoxycarbonyl)amino]butyl}-5-methoxyisoxazolidine-5-carboxylate
(5h). Prepared according to GP B3. Yield: 74%. Yellow oil. [a]2D4 ¼ þ39.6 (c ¼ 1.13, CHCl3). IR: 3374,
2976, 2935, 1751, 1707, 1520, 1455. 1H-NMR (400 MHz): 4.55 (br., 1 H); 3.83 (s, 3 H); 3.51 – 3.39 (m, 1 H);
3.35 (s, 3 H); 3.19 – 3.05 (m, 2 H); 2.66 (dd, J ¼ 13.3, 8.4, 1 H); 1.99 (dd, J ¼ 13.3, 7.5, 1 H); 1.71 – 1.58 (m,
1 H); 1.58 – 1.48 (m, 3 H); 1.45 (s, 9 H); 1.42 – 1.39 (m, 2 H). 13C-NMR (100 MHz): 168.4; 156.0; 108.0;
60.7; 52.7; 51.8; 47.9; 40.2; 31.2; 30.0; 28.4; 26.7; 24.4. HR-ESI-MS: 333.2029 ([M þ H]þ, C15H29N2O6þ ;
calc. 333.2020).
Methyl (3S,5R)-3-[3-(Benzoyloxy)propyl]-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulofuranosyl)-5-
methoxyisoxazolidine-5-carboxylate (4i). Prepared according to GP A. Yield: 49%. White solid. M.p.
104.58. [a]2D0 ¼ þ5.5 (c ¼ 1.00, CHCl3). IR: 2985, 1750, 1718, 1452, 1372, 1276, 1209, 1069, 715. 1H-NMR
(400 MHz): 8.10 – 7.39 (m, 5 H); 5.01 (d, J ¼ 6.0, 1 H); 4.76 – 4.68 (m, 1 H); 4.62 (s, 1 H); 4.40 – 4.22 (m,
3 H); 4.21 – 4.19 (m, 1 H); 4.16 – 4.06 (m, 1 H); 3.83 (s, 3 H); 3.36 (s, 3 H); 2.76 – 2.65 (m, 1 H); 2.29 – 2.13
(m, 1 H); 1.98 – 1.57 (m, 6 H); 1.43 (s, 3 H); 1.29 – 1.25 (m, 6 H); 1.21 (s, 3 H). 13C-NMR (100 MHz):
213.1; 169.9; 166.3; 133.1; 130.2; 129.1; 128.6; 112.6; 109.5; 106.2; 97.9; 82.8; 82.5; 80.3; 75.5; 65.8; 64.3;
61.8; 52.7; 52.0; 44.2; 30.2; 26.8; 26.3; 25.0; 24.5. HR-ESI-MS: 588.2415 ([M þ Na]þ, C32H54N4NaO1þ3
;
calc. 588.2415).
Methyl (3S,5R)-3-[3-(Benzoyloxy)propyl]-5-methoxyisoxazolidine-5-carboxylate (5i). Prepared
according to GP B2. Yield: 92%. Clear oil. IR: 2985, 1750, 1718, 1452, 1372, 1276, 1209, 1069, 715.
1H-NMR (400 MHz): 8.10 – 7.39 (m, 5 H); 5.5 – 5.59 (br. s, 1 H); 4.31 (t, 2 H); 3.81 (s, 3 H); 3.56 – 3.49 (m,
1 H); 3.36 (s, 3 H); 2.71 – 2.62 (m, 1 H); 2.06 – 1.92 (m, 1 H); 1.83 – 1.62 (m, 6 H). 13C-NMR (100 MHz):
166.5; 133.3; 130.2; 129.9; 128.5; 107.8; 64.3; 60.6; 53.0; 52.1; 48.1; 28.1; 26.8.
Methyl (3S,5R)-3-{3-[N’,N’’-Bis(tert-butoxycarbonyl)carbamimidamido]propyl}-N-(2,3 :5,6-di-O-
isopropylidene-b-d-gulofuranosyl)-5-methoxyisoxazolidine-5-carboxylate (4j). A soln. of 4i (2.54 g,
4.50 mmol, 1.00 equiv.) in 45 ml of MeOH (0.1m) was added a freshly prepared soln. of 340 mg of Na in
6.8 ml of MeOH (2.2m Na in MeOH) at 08 for 1 h. The reaction was quenched by the addition of dry ice,
and the mixture was allowed to slowly warm to r.t. The soln. was poured into aq. NH4Cl and extracted
with AcOEt (2 ꢁ 30 ml). The crude product was purified by FC (hexanes/AcOEt 1:1 to 7:3; Rf 0.15) to
give 4j-1 (1.904 g, 92%). To a soln. of 4j-1 (4.11 mmol) in anh. THF (0.1m), cooled at 08, was added Ph3P
(4.5 mmol, 1.1 equiv.). The mixture was stirred for 5 min at 08, and then DEAD (4.5 mmol, 1.1 equiv.)
and DPPA (4.5 mmol, 1.1 equiv.) were added dropwise. The mixture was allowed to warm slowly to r.t.
under stirring for 12 h, and the soln. was concentrated in vacuo. The crude residue was purified by FC
(hexanes/AcOEt 7:3) to afford 4j-2 (1.62 g, 4.8 mmol, 84%). To a soln. of 4j-2 (1.40 g, 2.87 mmol,
1.00 equiv.) in 14.3 ml of THF (0.20m) were added Ph3P (2.26 g, 8.62 mmol, 3.00 equiv.), H2O
(10.0 equiv.), and isothiourea 16 (916 mg, 3.16 mmol, 1.10 equiv.), and the mixture was heated to 658
while stirring for 1 h. EtNiPr2 (1.00 equiv.) was added, and the mixture was stirred for 90 min. The
mixture was poured into 25.0 ml of aq. NH4Cl and extracted with CH2Cl2 (3 ꢁ 30 ml), and the org. layers
were combined, dried (Na2SO4), filtered, and evaporated. The crude product was purified by FC
(hexanes/AcOEt 3 :1) to give 4j (951 mg, 48%). White solid. IR: 3335, 2980, 2936, 1750, 1417, 1369, 1210,
1054. 1H-NMR (400 MHz): 11.47 (s, 1 H); 8.40 – 8.25 (m, 1 H); 5.02 (d, J ¼ 6.0, 1 H); 4.71 (dd, J ¼ 5.6,
3.6, 1 H); 4.63 (s, 1 H); 4.33 (dd, J ¼ 15.2, 6.8, 1 H); 4.19 (dd, J ¼ 8.4, 6.8, 1 H); 4.07 (dd, J ¼ 8.4, 4.0,
1 H); 3.80 (s, 3 H); 3.71 (dd, J ¼ 8.4, 6.8, 1 H); 3.63 – 3.58 (m, 1 H); 3.49 – 3.41 (m, 1 H); 3.35 (s, 3 H);
2.67 (dd, J ¼ 13.2, 4.44, 1 H); 2.22 (dd, J ¼ 13.2, 2.0, 1 H); 1.89 – 1.51 (m, 4 H); 1.49 (s, 9 H); 1.47 (s, 9 H);
1.46 (s, 3 H); 1.38 (s, 3 H); 1.36 (s, 3 H); 1.30 (s, 3 H). 13C-NMR (100 MHz): 169.7; 163.8; 156.3; 153.4;
112.9; 109.9; 106.6; 97.8; 84.6; 84.2; 83.2; 80.4; 79.4; 75.9; 66.2; 61.7; 53.2; 52.2; 44.3; 40.9; 31.1; 28.5; 28.2;
27.1; 26.9; 26.3; 25.7; 25.1. HR-ESI-MS: 703.3779 ([M þ H]þ, C32H55N4ON1þ3 ; calc. 703.3766).
Methyl (3S,5R)-3-{3-[N’,N’’-Bis(tert-butoxycarbonyl)carbamimidamido]propyl}-5-methoxyisoxazo-
lidine-5-carboxylate (5j). Prepared according to GP B4. Yield: 77%. Yellow oil. [a]2D2 ¼ þ26.3 (c ¼ 0.89,
CHCl3). IR: 3334, 2930, 1753, 1721, 1414, 1367. 1H-NMR (400 MHz)6): 11.48 (br. s, 1 H); 8.33 (br. s, 1 H);
5.55 (br. s, 1 H); 3.82 (s, 3 H); 3.54 – 3.39 (m, 3 H); 3.34 (s, 3 H); 2.66 (dd, J ¼ 13.3, 8.4, 1 H#); 2.55 (dd, J ¼
13.3, 7.6, 1 H*); 1.99 (br., 1 H); 1.76 – 1.57 (m, 4 H); 1.49 (s, 9 H); 1.49 (s, 9 H); 1.33 – 1.18 (m, 2 H); 0.97 –
0.73 (m, 2 H). 13C-NMR (100 MHz): 163.6; 156.2; 153.3; 130.9; 128.8; 108.0; 83.2; 79.3; 60.5; 52.8; 51.9;
47.8; 40.5; 29.7; 28.3; 28.1; 26.9. HR-ESI-MS: 461.2611 ([M þ H]þ, C20H37N4O8þ ; calc. 461.2611).

Helvetica Chimica Acta – Vol. 95 (2012)
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tert-Butyl 3-{[(3S,5R)-N-(2,3 :5,6-Di-O-isopropylidene-b-d-gulofuranosyl)-5-methoxy-5-(methoxy-
carbonyl)isoxazolidin-3-yl]methyl}-1H-indole-1-carboxylate (4k). Prepared according to GP A. Yield:
57%. White crystalline solid. M.p. 1048. [a]2D0 ¼ þ24.3 (c ¼ 1.00, CHCl3). IR: 2982, 2936, 1733, 1454, 1370,
1309, 1257, 1159, 1088. 1H-NMR (400 MHz): 8.09 (br. s, 1 H); 7.65 (d, J ¼ 7.6, 1 H); 7.40 (s, 1 H); 7.28 (t,
J ¼ 7.2, 1 H); 7.21 (t, J ¼ 7.2, 1 H); 5.02 (d, J ¼ 6.0, 1 H); 4.68 (s, 1 H); 4.65 – 4.62 (m, 1 H); 4.34 – 4.28 (m,
1 H); 4.16 – 4.12 (m, 1 H); 3.98 – 3.90 (m, 1 H); 3.87 (dd, J ¼ 8.8, 4.0, 1 H); 3.78 (s, 3 H); 3.59 – 3.54 (m,
1 H); 3.44 (s, 3 H); 3.14 (dd, J ¼ 14.0, 5.6, 1 H); 2.96 (dd, J ¼ 14.0, 9.6, 1 H); 2.51 (dd, J ¼ 13.2, 8.0, 1 H);
2.37 (dd, J ¼ 13.6, 2.4, 1 H); 1.64 (s, 9 H); 1.44 (s, 3 H); 1.35 (s, 3 H); 1.32 (s, 3 H); 1.30 (s, 3 H). 13C-NMR
(100 MHz): 169.2; 149.8; 135.7; 131.4; 130.7; 124.5; 123.9; 122.6; 119.9; 117.8; 115.3; 112.9; 109.8; 106.6;
97.8; 84.4; 83.7; 80.4; 75.7; 66.1; 61.2; 53.2; 52.3; 43.7; 29.8; 28.3; 26.9; 26.3; 25.7; 25.1. HR-ESI-MS:
655.2822 ([M þ Na]þ, C32H44N2NaO1þ1 ; calc. 655.2843).
tert-Butyl 3-{[(3S,5R)-5-Methoxy-5-(methoxycarbonyl)isoxazolidin-3-yl]methyl}-1H-indole-1-car-
boxylate (5k). Prepared according to GP B2. Yield: 80%. Clear oil. [a]2D0 ¼ þ44.4 (c ¼ 1.00, CHCl3).
IR: 2960, 1734, 1452, 1372, 1309, 1259, 1157, 1083, 768. 1H-NMR (400 MHz): 8.12 (br. s, 1 H); 7.52 (d, J ¼
7.6, 1 H); 7.46 (s, 1 H),7.32 (t, J ¼ 7.2, 1 H); 7.24 (t, J ¼ 7.2, 1 H); 3.98 – 3.86 (m, 1 H); 3.80 (s, 3 H); 3.57 (s,
3 H); 3.10 (dd, J ¼ 9.2, 5.6, 1 H); 2.89 (dd, J ¼ 8.0, 6.8, 1 H); 2.62 (dd, J ¼ 8.4, 4.8, 1 H); 2.19 (dd, J ¼ 6.8,
6.4, 1 H); 1.67 (s, 9 H). 13C-NMR (100 MHz): 168.5; 149.9; 135.7; 130.4; 124.9; 123.8. 122.8; 119.0; 116.6;
115.6; 108.3; 83.9; 60.3; 53.1; 52.2; 47.7; 29.9; 28.5; 27.3. HR-ESI-MS: 413.1687 ([M þ Na]þ,
C32H44N2NaOþ11 ; calc. 413.1691).
Methyl (3R,5R)-3-{[(tert-Butoxycarbonyl)oxy]methyl}-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulo-
furanosyl)-5-methoxyisoxazolidine-5-carboxylate (4l). Prepared according to GP A. Yield: 36%. White
1
crystalline solid. H-NMR (400 MHz): 5.01 (d, J ¼ 6.0, 1 H); 4.76 – 4.68 (m, 2 H); 4.40 – 4.35 (m, 1 H);
4.30 – 4.18 (m, 2 H); 4.16 – 4.01 (m, 1 H); 4.06 – 3.95 (m, 2 H); 3.83 (s, 3 H); 3.76 – 3.7 (m, 1 H); 3.38 (s,
3 H); 2.69 (dd, J ¼ 13.6, 5.6, 1 H); 2.38 (dd, J ¼ 13.6, 1.6, 1 H); 1.47 – 1.44 (m, 15 H); 1.39 (s, 3 H); 1.32 (s,
3 H).
Methyl (3R,5R)-3-{[(tert-Butoxycarbonyl)oxy]methyl}-5-methoxyisoxazolidine-5-carboxylate (5l).
Prepared according to GP B3. Yield: 61%. Clear oil. 1H-NMR (400 MHz): 6.19 – 5.95 (br. s, 1 H); 4.30 –
4.15 (m, 1 H); 3.83 (s, 3 H); 3.82 – 3.76 (m, 1 H); 3.37 (s, 3 H); 2.61 (dd, J ¼ 13.6, 5.6, 1 H); 2.27 (m, 1 H);
1.49 (s, 9 H).
tert-Butyl 4-[(3R,5R)-N-(2,3 :5,6-Di-O-isopropylidene-b-d-gulofuranosyl)-5-Methoxy-5-(methoxy-
carbonyl)isoxazolidin-3-yl]piperidine-1-carboxylate (4m). Prepared according to GP A. Yield: 39%.
White crystalline solid. M.p. 113 – 1148. [a]2D0 ¼ þ5.1 (c ¼ 1.00, CHCl3). IR: 3489, 2982, 2973, 1751, 1692,
1427, 1369, 1282, 1213, 1166, 1087, 1066, 848, 755. 1H-NMR (400 MHz): 5.01 (d, J ¼ 6.0, 1 H); 4.68 (dd,
J ¼ 6.0, 3.6, 1 H); 4.61 (s, 1 H); 4.37 – 4.32 (m, 1 H); 4.21 (dd, J ¼ 8.4, 6.8, 1 H); 4.11 – 4.02 (m, 2 H); 4.05
(dd, J ¼ 8.4, 4.0, 1 H); 3.81 (s, 3 H); 3.75 – 3.71 (m, 1 H); 3.38 – 3.33 (m, 1 H); 3.33 (s, 3 H); 2.70 – 2.60 (m,
2 H); 2.50 (dd, J ¼ 14.0, 8.0, 1 H); 2.42 (dd, J ¼ 13.6, 2.0, 1 H); 1.90 – 1.87 (m, 1 H); 1.80 – 1.77 (m, 1 H);
1.67 – 1.62 (m, 1 H); 1.44 (s, 3 H); 1.42 (s, 3 H); 1.42 (s, 9 H); 1.37 (s, 3 H); 1.30 (s, 3 H); 1.15 – 1.04 (m,
2 H). 13C-NMR (125 MHz): 169.7; 154.8; 112.9; 110.1; 107.0; 97.9; 84.7; 84.2; 80.4; 79.4; 75.8; 66.2; 53.2;
52.2; 40.0; 37.7; 28.9; 28.6; 26.9; 26.3; 25.4; 25.18. HR-ESI-MS: 609.2971 ([M þ Na]þ, C28H46N2NaO1þ1
;
calc. 609.3002).
tert-Butyl 4-[(3R,5R)-5-Methoxy-5-(methoxycarbonyl)isoxazolidin-3-yl]piperidine-1-carboxylate
(5m). Prepared according to GP B2. Yield: 83%. Clear oil. [a]2D0 ¼ þ44.6 (c ¼ 1.00, CHCl3). IR: 3484,
3207, 2976, 2937, 2854, 1751, 1689, 1426, 1366, 1275, 1242, 1161, 1073, 732. 1H-NMR (400 MHz): 4.13 – 4.02
(m, 2 H); 3.81 (s, 3 H); 3.33 (s, 3 H); 3.27 – 3.22 (m, 1 H); 2.70 – 2.60 (m, 2 H); 2.58 (dd, J ¼ 13.2, 8.4,
1 H); 2.06 (dd, J ¼ 13.2, 7.6, 1 H); 1.82 – 1.77 (m, 1 H); 1.60 – 1.56 (m, 1 H); 1.55 – 1.53 (m, 1 H); 1.44 (s,
9 H); 1.28 – 1.21 (m, 2 H). 13C-NMR (125 MHz): 168.5; 15439; 108.1; 79.8; 65.4; 53.0; 52.1; 46.1; 38.9;
30.4; 29.6; 28.6. HR-ESI-MS: 367.1829 ([M þ Na]þ, C16H28N2NaO6þ ; calc. 367.1847).
Methyl (3R,5R)-3-[2-(tert-Butoxy)-2-oxoethyl]-N-(2,3 :5,6-di-O-isopropylidene-b-d-gulofurano-
syl)-5-methoxyisoxazolidine-5-carboxylate (4n). Compound 4n-1 was prepared according to GP A using
b-sulfanylaldehyde 16 (white solid, yield: 32%). To a soln. of 4n-1 (0.93 mmol) in CH2Cl2 (0.10m) was
added 0.29m mCPBA in CH2Cl2 (0.93 mmol, 1.0 equiv.) dropwise at ꢀ 208. The soln. was stirred for
30 min. The reaction was quenched by the addition of sat. NaHCO3 soln., and the mixture was extracted
with CH2Cl2 (3ꢁ). The org. layers were combined, washed with brine, dried (Na2SO4), and concentrated

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Helvetica Chimica Acta – Vol. 95 (2012)
in vacuo to give 4n-2 as a mixture of diastereoisomers (490 mg, 95%). To a soln. of 4n-2 (0.88 mmol) and
2,6-lutidine (2.29 mmol, 2.6 equiv.) in MeCN (0.17m) was added 0.50m TFAA in MeCN (1.76 mmol,
2.0 equiv.) dropwise at 08. After 10 min, further TFAA (0.5 equiv.) was added, stirring was continued for
10 min., and sat. NaHCO3 soln. and HgCl2 (1.94 mmol, 2.2 equiv.) were added, and the soln. was stirred at
r.t. for 2 h. The resulting mixture was filtered through a pad of Celite and extracted with AcOEt (3ꢁ).
The org. layers were combined, washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude
product was purified by FC (hexanes/AcOEt 3 :1) to give 4n-3 as a pale yellow oil (272 mg, 69%). To a
soln. of 4n-3 (0.61 mmol) and 2-methylbut-2-ene (6.1 mmol, 10 equiv.) in tBuOH/H2O (3 :1, 0.09m) were
added NaClO2 (3.00 mmol, 4.9 equiv.) and NaH2PO4 (3.30 mmol, 5.4 equiv.) at 08. After 20 min, the soln.
was treated with ice and extracted with AcOEt (3ꢁ). The org. layers were combined, washed with brine,
dried (Na2SO4), and concentrated in vacuo to give 4n-4 as a pale yellow oil (270 mg, 97%). To a soln. of
4n-4 (0.59 mmol) in toluene (0.1m) was added 2-(tert-butyl)-1,3-diisopropylisourea (1.17 mmol,
2.0 equiv.), and the mixture was stirred at r.t. for 10 h. Further 2-(tert-butyl)-1,3-diisopropylisourea
(1.0 equiv.) was added, and stirring was continued for 6 h. The solvent was concentrated under reduced
pressure, and the residue was purified by FC (hexanes/AcOEt 5 :1) to give 4n (182 mg, 57%). Pale yellow
oil. [a]2D0 ¼ þ21.9 (c ¼ 1.02, CHCl3). IR: 2983, 2937, 1751, 1733, 1370, 1259. 1H-NMR (500 MHz): 4.98 (d,
J ¼ 6.5, 1 H); 4.69 – 4.66 (m, 1 H); 4.39 – 4.35 (m, 1 H); 4.21 – 4.18 (m, 1 H); 4.11 (dd, J ¼ 4.0, 8.5, 1 H);
3.90 – 3.85 (m, 1 H); 3.80 (s, 3 H); 3.74 – 3.71 (m, 1 H); 3.35 (s, 3 H); 2.85 – 2.79 (m, 1 H); 2.50 (dd, J ¼ 8.5,
16.5, 1 H); 2.29 (dd, J ¼ 4.0, 13.5, 1 H); 1.45 (s, 3 H); 1.44 (s, 3 H); 1.42 (s, 9 H); 1.38 (s, 3 H); 1.30 (s, 3 H).
13C-NMR (125 MHz): 170.3; 169.0; 112.8; 109.9; 105.6; 98.5; 84.3; 84.0; 75.8; 66.2; 58.9; 53.1; 52.1; 45.0;
39.5; 28.2; 26.9; 26.2; 25.5; 24.0. HR-ESI-MS: 540.2430 ([M þ Na]þ, C24H39NNaO1þ1 ; calc. 540.2421).
Methyl (3R,5R)-3-[2-(tert-Butoxy)-2-oxoethyl]-5-methoxyisoxazolidine-5-carboxylate (5n). Pre-
pared according to GP B3. Yield: 66%. Yellow oil. [a]2D7 ¼ þ64.3 (c ¼ 0.825, CHCl3). IR: 2979, 2952,
1751, 1728, 1437, 1369. 1H-NMR (500 MHz): 3.78 (s, 3 H); 3.73 (br. s, 1 H); 3.30 (s, 3 H); 2.67 (dd, J ¼ 8.5,
13.5, 1 H); 2.55 (dd, J ¼ 6.0, 16.0, 1 H); 2.43 (dd, J ¼ 9.0, 15.5, 1 H); 2.07 (br. s, 1 H); 1.40 (s, 9 H).
13C-NMR (125 MHz): 169.7; 168.3; 112.6; 108.2; 81.6; 57.0; 52.9; 52.0; 47.0; 36.7; 28.2. HR-ESI-MS:
298.1275 ([M þ Na]þ, C12H21NNaOþ6 ; calc. 298.1267).
3.2. Preparation of Enantiomerically Pure Isoxazolidine Monomers with unlike-Configured Residues
(Scheme 6). Methyl (3R,5S)-N-(2,3 :5,6-Di-O-isopropylidene-b-l-gulofuranosyl)-5-methoxy-3-methyl-
isoxazolidine-5-carboxylate (7a). Prepared according to GP A. Yield: 46%. White crystalline solid.
M.p. 103 – 1048. [a]2D0 ¼ ꢀ55.4 (c ¼ 1.00, CHCl3). IR: 2986, 1751, 1455, 1372, 1254, 1210, 1066, 894.
1H-NMR (400 MHz): 5.01 (d, J ¼ 6.0, 1 H); 4.71 (dd, J ¼ 6.0, 4.0, 1 H); 4.68 (s, 1 H); 4.40 – 4.35 (m, 1 H);
4.20 (dd, J ¼ 8.4, 6.4, 1 H); 4.11 (dd, J ¼ 8.4, 4.0, 1 H); 3.81 (s, 3 H); 3.73 (dd, J ¼ 8.4, 6.4, 1 H); 3.55 –
3.48 (m, 1 H); 3.37 (s, 3 H); 2.73 (dd, J ¼ 13.2, 7.6, 1 H); 2.20 (dd, J ¼ 13.6, 6.0, 1 H); 1.47 (s, 3 H); 1.42 (s,
3 H); 1.38 (s, 1 H); 1.32 (d, J ¼ 6.0, 3 H); 1.31 (s, 3 H). 13C-NMR (100 MHz): 169.3; 112.9,109.9; 105.2;
98.9; 84.4; 84.0; 80.5; 75.9; 66.2; 58.7; 53.1; 52.2; 47.2; 26.9; 26.3; 25.6; 25.0; 19.1. HR-ESI-MS: 440.1911
([M þ Na]þ, C19H31NNaOþ9 ; calc. 440.1891).
Methyl (3R,5S)-5-Methoxy-3-methylisoxazolidine-5-carboxylate (8a). Prepared according to GP B1.
Yield: 79%. Clear oil. [a]2D0 ¼ ꢀ74.1 (c ¼ 1.00, CHCl3). IR: 3214, 2955, 2838, 1749, 1438, 1068. 1H-NMR
(400 MHz)6): 5.46 (s, 1 H#); 3.74 (s, 3 H#); 3.60 – 3.51 (m, 1 H*); 3.50 – 3.43 (m, 1 H#); 3.25 (s, 3 H#); 2.60
(dd, J ¼ 13.2, 8.4, 1 H#); 2.47 (dd, J ¼ 13.2, 7.2, 1 H*); 2.05 (dd, J ¼ 13.2, 8.0, 1 H*); 1.87 (dd, J ¼ 13.2, 8.0,
1 H#); 1.16 (d, J ¼ 6.4, 3 H#); 1.14 (d, J ¼ 6.4, 3 H*). 13C-NMR (100 MHz)6): 168.5; 108.6#; 108.0*; 56.3#;
55.28*; 53.0#; 52.9*; 52.0#; 51.8*; 49.5#; 49.1*; 16.1#. HR-EI-MS: 175.0839 ([M þ Na]þ, C7H13NNaOþ4 ; calc.
175.0844).
Methyl (3S,5S)-N-(2,3 :5,6-Di-O-isopropylidene-b-l-gulofuranosyl)-3-isopropyl-5-methoxyisoxazo-
lidine-5-carboxylate (7b). Prepared according to GP A. Yield: 52%. White crystalline solid. M.p. 111 –
1128. [a]2D0 ¼ ꢀ6.8 (c ¼ 1.00, CHCl3). IR: 2983, 2873, 1751, 1455, 1371, 1210, 1068, 895, 733. H-NMR
1
(400 MHz): 5.04 (d, J ¼ 6.0, 1 H); 4.71 (dd, J ¼ 6.0, 4.0, 1 H); 4.65 (s, 1 H); 4.39 – 4.33 (m, 1 H); 4.21 (dd,
J ¼ 8.4, 6.8, 1 H); 4.12 (dd, J ¼ 8.4, 4.0, 1 H); 3.82 (s, 3 H); 3.74 (dd, J ¼ 8.4, 6.4, 1 H); 3.33 (s, 3 H);
3.28 – 3.23 (m, 1 H); 2.54 – 2.42 (m, 2 H); 2.01 – 1.92 (m, 1 H); 1.46 (s, 3 H); 1.40 (s, 3 H); 1.38 (s, 3 H);
1.31 (s, 3 H); 0.96 (d, J ¼ 6.4, 3 H); 0.90 (d, J ¼ 6.8, 3 H). 13C-NMR (100 MHz): 170.0; 112.8; 110.0;
106.9; 97.9; 84.5; 84.2; 80.5; 75.9; 68.1; 66.2; 53.2; 52.2; 40.6; 29.7; 26.8; 26.3; 25.5; 25.2; 21.4; 19.3. HR-
ESI-MS: 468.2225 ([M þ Na]þ, C21H35NNaO9þ ; calc. 468.2204).

Helvetica Chimica Acta – Vol. 95 (2012)
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Methyl (3S,5S)-3-Isopropyl-5-methoxyisoxazolidine-5-carboxylate (8b). Prepared according to
GP B1. Yield: 86%. Clear oil. [a]2D0 ¼ ꢀ98.8 (c ¼ 1.00, CHCl3). IR: 3213, 2959, 1752, 1466, 1438, 1267,
1219, 1070, 1047. 1H-NMR (400 MHz): 5.61 (br. s, 1 H); 3.78 (s, 3 H); 3.29 (s, 3 H); 3.23 – 3.10 (m, 3 H);
2.54 (dd, J ¼ 8.3, 13.4, 1 H); 2.06 – 1.96 (m, 1 H); 1.72 – 1.61 (m, 1 H); 0.96 (d, J ¼ 6.8, 1 H); 0.90 (d, J ¼
6.4, 1 H). 13C-NMR (100 MHz): 168.8; 108.53; 67.6; 53.2; 52.2; 51.9; 46.8; 45.4; 30.9; 21.1; 20.4. HR-ESI-
MS: 204.1230 ([M þ Na]þ, C9H17NNaOþ4 ; calc. 204.1230).
Methyl (3R,5S)-N-(2,3 :5,6-Di-O-isopropylidene-b-l-gulofuranosyl)-5-methoxy-3-(2-methylpropyl)-
isoxazolidine-5-carboxylate (7c). Prepared according to GP A. Yield: 81%. White crystalline solid. M.p.
119 – 1218. [a]2D0 ¼ ꢀ3.2 (c ¼ 1.00, CHCl3). IR: 2987, 2954, 1756, 1454, 1381, 1372, 1219, 1178, 1086, 873,
741. 1H-NMR (400 MHz): 5.03 (d, J ¼ 6.0, 1 H); 4.69 (dd, J ¼ 6.0, 4.0, 1 H); 4.65 (s, 1 H); 4.39 – 4.34 (m,
1 H); 4.20 (dd, J ¼ 8.4, 6.8, 1 H); 4.06 (dd, J ¼ 8.4, 3.6, 1 H); 3.81 (s, 3 H); 3.72 – 3.66 (m, 1 H); 3.35 (s,
3 H); 2.69 (dd, J ¼ 13.6, 8.0, 1 H); 2.18 (dd, J ¼ 13.2, 2.4, 1 H); 1.83 – 1.76 (m, 1 H); 1.69 – 1.61 (m, 1 H);
1.45 (s, 3 H); 1.40 (s, 3 H); 1.36 (s, 3 H) 1.30 (s, 3 H); 1.22 – 1.17 (m, 1 H); 0.93 (dd, J ¼ 6.4, 5.6, 6 H).
13C-NMR (100 MHz): 170.0; 112.8; 109.9; 106.8; 97.8; 84.5; 84.3; 80.4; 75.7; 66.2; 59.9; 53.2; 52.3; 44.8;
42.9; 26.8; 26.3; 25.9; 25.4; 25.1; 23.3; 22.2. HR-ESI-MS: 482.2383 ([M þ Na]þ, C22H37NNaO9þ ; calc.
482.2361).
Methyl (3R,5S)-5-Methoxy-3-(2-methylpropyl)isoxazolidine-5-carboxylate (8c). Prepared according
to GP B1. Yield: 80%. Clear oil. [a]2D0 ¼ ꢀ76.3 (c ¼ 1.00, CHCl3). IR: 3215, 2955, 2872, 2842, 1752, 1439,
1
1387, 1267, 1070, 810. H-NMR (400 MHz)6): 6.15 (s, 1 H*); 5.46 (s, 1 H#); 3.79 (s, 3 H#); 3.77 (s, 3 H*);
3.59 – 3.52 (m, 1 H*); 3.52 – 3.42 (m, 1 H#); 3.30 (s, 3 H#); 3.27 (s, 3 H*); 2.62 (dd, J ¼ 13.2, 8.0, 1 H#); 2.50
(dd, J ¼ 13.2, 7.2, 1 H*); 2.04 (m, 1 H*); 1.91 (m, 1 H#); 1.68 – 1.58 (m, 1 H#); 1.48 – 1.42 (m, 1 H#); 1.37 –
1.30 (m, 1 H#); 0.89 (dd, J ¼ 10, 6.4, 6 H#). 13C-NMR (100 MHz): 168.6; 108.2; 59.4; 53.0; 52.9; 52.0; 51.9;
48.6; 47.9; 40.7; 26.7; 23.0; 22.9; 22.8. HR-ESI-MS: 240.1212 ([M þ Na]þ, C10H19NNaO4þ ; calc. 240.1206).
Methyl (3R,5S)-3-Benzyl-N-(2,3 :5,6-di-O-isopropylidene-b-l-gulofuranosyl)-5-methoxyisoxazoli-
dine-5-carboxylate (7d). Prepared according to GP A. Yield: 53%. White crystalline solid. M.p. 116 –
1188. [a]2D0 ¼ þ15.8 (c ¼ 1.00, CHCl3). IR: 3217, 3027, 2951, 1749, 1454, 1438, 1067. 1H-NMR
(400 MHz): 7.29 – 7.17 (m, 5 H); 5.01 (d, J ¼ 6.4, 1 H); 4.70 (s, 1 H); 4.65 (dd, J ¼ 6.0, 4.0, 1 H); 4.33 –
4.29 (m, 1 H); 4.15 (dd, J ¼ 8.0, 6.8, 1 H); 3.88 – 3.77 (m, 1 H); 3.79 (s, 3 H); 3.61 (dd, J ¼ 8.4, 6.8,
1 H); 3.42 (s, 3 H); 3.11 (dd, J ¼ 13.6, 8.0, 1 H); 2.82 (dd, J ¼ 13.2, 8.8, 1 H); 2.51 (dd, J ¼ 13.6, 8.0, 1 H);
2.31 (dd, J ¼ 13.6, 2.8, 1 H); 1.45 (s, 3 H); 1.41 (s, 3 H); 1.36 (s, 3 H); 1.30 (s, 3 H). 13C-NMR (100 MHz):
169.5; 138.8; 129.7; 128.6; 126.5; 112.9; 109.9; 106.6; 97.8; 84.4; 84.2; 80.4; 75.8; 66.2; 63.0; 53.2; 52.2; 43.5;
39.9; 27.1; 26.3; 25.6; 25.1. HR-ESI-MS: 516.2229 ([M þ Na]þ, C25H35NNaO9þ ; calc. 516.2204).
Methyl (3R,5S)-3-Benzyl-5-methoxyisoxazolidine-5-carboxylate (8d). Prepared according to GP B1.
Yield: 94%. Clear oil. [a]2D0 ¼ ꢀ89.2 (c ¼ 1.00, CHCl3). IR: 3028, 2952, 1749, 1604, 1498, 1439, 1268, 1209,
1153, 932, 702. 1H-NMR (400 MHz)6): 7.31 – 7.18 (m, 5 H#); 6.21 (s, 1 H*); 5.69 (s, 1 H#); 3.84 (s, 3 H*);
3.78 (s, 3 H#); 3.34 (s, 3 H#); 3.33 (s, 3 H*); 3.03 (dd, J ¼ 13.2, 5.6, 1 H#); 3.03 – 2.98 (m, 1 H*); 2.79 – 2.71
(m, 1 H*); 2.72 – 2.67 (m, 1 H#); 2.55 – 2.48 (m, 1 H#); 2.46 – 2.42 (m, 1 H*); 2.26 (m, 1 H*); 2.10 (m,
1 H#). 13C-NMR (100 MHz): 168.2; 137.6; 129.5; 129.1; 128.9; 128.7; 126.9; 108.3; 107.9; 62.0; 61.1; 53.1;
53.0; 52.1; 51.9; 47.5; 37.4. HR-ESI-MS: 247.1050 ([M þ Na]þ, C13H17NNaO4þ ; calc. 274.1049).
Methyl (3R,5S)-3-[3-(Benzoyloxy)propyl]-N-(2,3 :5,6-di-O-isopropylidene-b-l-gulofuranosyl)-5-
methoxyisoxazolidine-5-carboxylate (7e). Prepared according to GP A. Yield: 20%. White crystalline
solid. M.p. 104.58. [a]2D0 ¼ ꢀ5.0 (c ¼ 1.00, CHCl3). IR: 2985, 1752, 1719, 1452, 1372, 1275, 1210, 1070, 847,
714. 1H-NMR (400 MHz): 8.10 – 7.39 (m, 5 H); 5.01 (d, J ¼ 6.0, 1 H); 4.76 – 4.68 (m, 1 H); 4.62 (s, 1 H);
4.40 – 4.22 (m, 3 H); 4.21 – 4.19 (m, 1 H); 4.16 – 4.06 (m, 1 H); 3.83 (s, 3 H); 3.36 (s, 3 H); 2.76 – 2.65 (m,
1 H); 2.29 – 2.13 (m, 1 H); 1.98 – 1.57 (m, 6 H); 1.43 (s, 3 H); 1.29 – 1.25 (m, 6 H); 1.21 (s, 3 H). 13C-NMR
(100 MHz): 213.1; 169.9; 166.3; 133.1; 130.2; 129.1; 128.6; 112.6; 109.5; 106.2; 97.9; 82.8; 82.5; 80.3; 75.5;
65.8; 64.3; 61.8; 52.7; 52.0; 44.2; 30.2; 26.8; 26.3; 25.0; 24.5. HR-ESI-MS: 588.2424 ([M þ Na]þ,
C32H54N4NaOþ13 ; calc. 588.2415).
Methyl (3R,5S)-3-[3-(Benzoyloxy)propyl]-5-methoxyisoxazolidine-5-carboxylate (8e). Prepared
according to GP B2. Yield: 92%. Clear oil. IR: 2985, 1750, 1718, 1452, 1372, 1276, 1209, 1069, 715.
1H-NMR (400 MHz): 8.10 – 7.39 (m, 5 H); 5.5 – 5.59 (br. s, 1 H); 4.31 (t, 2 H); 3.81 (s, 3 H); 3.56 – 3.49 (m,
1 H); 3.36 (s, 3 H); 2.71 – 2.62 (m, 1 H); 2.06 – 1.92 (m, 1 H); 1.83 – 1.62 (m, 6 H). 13C-NMR (100 MHz):
166.5; 133.3; 130.2; 129.9; 128.5; 107.8; 64.3; 60.6; 53.0; 52.1; 48.1; 28.1; 26.8.

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Helvetica Chimica Acta – Vol. 95 (2012)
Methyl (3R,5S)-N-(2,3 :5,6-Di-O-isopropylidene-b-l-gulofuranosyl)-3-(4-hydroxybenzyl)-5-meth-
oxyisoxazolidine-5-carboxylate (7f). Bn-Protected 7f-1 was prepared according to GP A (yield: 27%).
To a soln. of 7f-1 (5.08 g, 8.50 mmol, 1.00 equiv.) in 3.0 ml of MeOH was added Pd/C (5.0 wt-%, 1.80 g,
0.10 equiv.), followed by dry MeOH (85.0 ml, 0.10m). The resulting black suspension was stirred
vigorously under H2 overnight. The soln. was filtered through Celite, and the solvent was evaporated. The
crude solid was recrystallized by dissolving in a minimal amount of hot AcOEt, followed by slowly
layering hexanes on top. Upon standing, white crystals formed which were filtered and dried in vacuo to
give 7f (3.50 g, 81.0 %). M.p. 1368. [a]2D0 ¼ þ17.0 (c ¼ 1.00, CHCl3). IR: 3408, 2988, 2938, 1750, 1516, 1440,
1373, 1264, 1211, 1087, 846, 756. 1H-NMR (400 MHz): 7.01 (d, J ¼ 8.4, 2 H); 6.72 (d, J ¼ 8.4, 2 H); 6.19 (s,
1 H); 4.99 (d, J ¼ 6.0, 1 H); 4.68 (s, 1 H); 4.65 – 4.62 (m, 1 H); 4.34 – 4.28 (m, 1 H); 4.16 – 4.12 (m, 1 H);
3.86 (dd, J ¼ 8.4, 4.0, 1 H); 3.77 – 3.60 (m, 1 H); 3.76 (s, 3 H); 3.67 – 3.61 (m, 1 H); 3.39 (s, 3 H); 2.98 (dd,
J ¼ 13.2, 6.4, 1 H); 2.72 (dd, J ¼ 13.6, 9.2, 1 H); 2.44 (dd, J ¼ 14.0, 8.0, 1 H); 2.26 (dd, J ¼ 14.0, 2.8, 1 H);
1.43 (s, 3 H); 1.41 (s, 3 H); 1.35 (s, 3 H); 1.28 (s, 3 H). 13C-NMR (100 MHz): 169.6; 154.7; 130.8; 130.4;
115.6; 112.9; 110.0; 106.6; 97.7; 84.3; 84.1; 80.4; 75.8; 66.2; 63.2; 53.3; 52.2; 43.3; 38.8; 27.0; 26.2; 25.5; 25.0.
HR-ESI-MS: 532.2137 ([M þ Na]þ, C25H35NNaO1þ0 ; calc. 532.2159).
Methyl (3R,5S)-3-(4-Hydroxybenzyl)-5-methoxyisoxazolidine-5-carboxylate (8f). Prepared accord-
ing to GP B2. Yield: 93%. Clear oil. [a]2D0 ¼ ꢀ 33.0 (c ¼ 1.00, CHCl3). IR: 3500 – 3300 (br.), 3208, 2953,
1
1750, 1516, 1269. H-NMR (400 MHz): 7.01 (d, J ¼ 8.4, 2 H); 6.72 (d, J ¼ 8.4, 2 H); 6.00 – 5.80 (br. s,
1 H); 3.81 (s, 3 H); 3.76 – 3.69 (m, 1 H); 3.36 (s, 3 H); 2.91 (dd, J ¼ 13.6, 6.0, 1 H); 2.71 (dd, 14.0, 8.0,
1 H); 2.56 (dd, J ¼ 13.6, 8.8, 1 H); 2.14 (dd, 13.2, 7.2, 1 H). 13C-NMR (100 MHz): 168.9; 155.1; 130.0;
128.9; 115.9; 108.2; 62.0; 53.1; 52.2; 47.1; 36.5. HR-ESI-MS: 290.1010 ([M þ Na]þ, C13H17NNaO5þ ; calc.
290.0998).
tert-Butyl 3-{[(3R,5S)-N-(2,3 :5,6-Di-O-isopropylidene-b-l-gulofuranosyl)-5-methoxy-5-(methoxy-
carbonyl)isoxazolidin-3-yl]methyl}-1H-indole-1-carboxylate (7g). Prepared according to GP A. Yield:
41%. White crystalline solid. M.p. 1028. [a]D20 ¼ ꢀ20.1 (c ¼ 1.00, CHCl3). 1H-NMR (400 MHz): 8.09 (br. s,
1 H); 7.66 (d, J ¼ 7.6, 1 H); 7.41 (s, 1 H); 7.29 (t, J ¼ 7.2, 1 H); 7.22 (t, J ¼ 7.2, 1 H); 5.02 (d, J ¼ 6.0, 1 H);
4.69 (s, 1 H); 4.65 – 4.62 (m, 1 H); 4.34 – 4.28 (m, 1 H); 4.16 – 4.12 (m, 1 H); 3.98 – 3.90 (m, 1 H); 3.87 (dd,
J ¼ 8.8, 4.0, 1 H); 3.79 (s, 3 H); 3.59 – 3.54 (m, 1 H); 3.45 (s, 3 H); 3.15 (dd, J ¼ 14.0, 5.6, 1 H); 2.97 (dd,
J ¼ 14.0, 9.6, 1 H); 2.52 (dd, J ¼ 13.2, 8.0, 1 H); 2.37 (dd, J ¼ 13.6, 2.4, 1 H); 1.65 (s, 9 H); 1.45 (s, 3 H);
1.36 (s, 3 H); 1.33 (s, 3 H); 1.31 (s, 3 H). 13C-NMR (100 MHz): 169.3; 149.8; 135.7; 131.4; 130.7; 124.5;
123.9; 122.6; 119.9; 117.8; 115.3; 112.9; 109.8; 106.6; 97.8; 84.4; 83.7; 80.4; 75.7; 66.1; 61.2; 53.2; 52.3; 43.7;
29.8; 28.3; 26.9; 26.3; 25.7; 25.1. HR-ESI-MS: 655.2821 ([M þ Na]þ, C32H44N2NaO1þ1 ; calc. 655.2843).
tert-Butyl 3-{[(3R,5S)-5-Methoxy-5-(methoxycarbonyl)isoxazolidin-3-yl]methyl}-1H-indole-1-car-
boxylate (8g). Prepared according to GP B2. Yield: 42%. Clear oil. [a]2D0 ¼ ꢀ47.7 (c ¼ 1.00, CHCl3).
IR: 2957, 1730, 1454, 1372, 1309, 1259, 1157, 1085, 749. 1H-NMR (400 MHz): 8.12 (br. s, 1 H); 7.52 (d, J ¼
7.6, 1 H); 7.46 (s, 1 H); 7.32 (t, J ¼ 7.2, 1 H); 7.24 (t, J ¼ 7.2, 1 H); 3.98 – 3.86 (m, 1 H); 3.80 (s, 3 H); 3.57
(s, 3 H); 3.10 (dd, J ¼ 9.2, 5.6, 1 H); 2.89 (dd, J ¼ 8.0, 6.8, 1 H); 2.62 (dd, J ¼ 8.4, 4.8, 1 H); 2.19 (dd, J ¼
6.8, 6.4, 1 H); 1.67 (s, 9 H). 13C-NMR (100 MHz): 168.4; 149.9; 135.7; 130.4; 124.9; 123.9. 122.9; 119.0;
116.6; 115.6; 108.3; 83.9; 60.3; 53.1; 52.2; 47.6; 29.9; 28.5; 27.3. HR-ESI-MS: 413.1684 ([M þ Na]þ,
C32H44N2NaOþ11 ; calc. 413.1691).
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Received August 17, 2012